Probing Gallic Acid for Its Broad Spectrum Applications
Sneha Choubey1, Soniya Goyal1, Lesley Rachel Varughese1, Vinod Kumar2,3, Anil K. Sharma1 and Vikas Beniwal1*

1Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala- 133207 (Haryana), India; 2Department of Chemistry, Maharishi Markandeshwar University, Mullana, Ambala- 133207 (Haryana), India; 3Department of Chemistry, M.N. College, Shahabad (M) – 136135, Haryana, India

Abstract: Gallic acid and its derivatives not only exhibit excellent antioxidant, anticarcinogenic, an- timutagenic, antimicrobial properties but also provide protection to the cells against oxidative stress.

A R T I C L E H I S T O R Y

Received: January 30, 2017 Revised: January 08, 2018 Accepted: January 15, 2018
DOI: 10.2174/1389557518666180330114010
Gallic acid (3, 4, 5-trihydroxybenzoic acid), a low molecular triphenolic compound emerged as an ef- ficient apoptosis inducing agent. The antimicrobial and other biological properties of gallic acid and its derivatives seemed to be linked with the hydrolysis of ester linkage between gallic acid and polyols like tannins hydrolyzed after ripening of many edible fruits. Gallic acid serves a natural defense mechanism against microbial infections and modulation of immune responses. The current review up- dates us with the diverse roles played by gallic acid, its antioxidant potential, action mechanism and more importantly the diverse array of applications in therapeutic and pharmaceutical areas.

Keywords: Antioxidant, anti-diabetic, anti-tyrosinase, antimicrobial properties, gallic acid, pharmaceutical areas.

1.INTRODUCTION
Gallic acid (Fig. 1), a yellowish white crystalline pheno- lic compound, has been reported to exhibit many important biological activities mostly imparted by the phenolic hy- droxyl groups. Owing to scavenging ability towards free radicals, gallic acid acts as an excellent antioxidant agent and is also responsible to many other important biological activities such as anti-carcinogenic, anti-inflammatory, anti-bacterial, anti-fungal, anti-diabetic, anti-tyrosinase, etc. [1-4].

HO O

HO OH
OH Gallic acid (1)

Fig. (1). Gallic acid structure.

It is quite noteworthy that gallic acid is non-toxic up to the level of 5000 mg/kg body weight, when given orally [4].

*Address correspondence to this author at the Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala- 133203 (Haryana), India; Tel: +919416768062; Fax: +911731274375;
E-mail: [email protected]
However, the only limitation is its poor solubility (11.5 mg/mL) [5]. To overcome this limitation Phiriyawirut and Phachamud (2011) reported electrospun fiber mats as a drug delivery carrier of gallic acid, providing a high surface area, resulting in improved solubility and release of gallic acid [6]. Recently, increased solubility of gallic acid has also been reported by dissolving it in N-methyl pyrrolidone (NMP) [7].
The major pharmaceutical application of gallic acid in- cludes manufacturing of analgesics, astringents and antimi- crobial agents. It is also used as a key synthetic intermediate for the production of pyrogallol and gallic acid esters used in foods, cosmetics, hair products, adhesives, and lubricants. It is extensively used as an ingredient of developer in photogra- phy and printing inks. It also serves as a precursor for the commercial production of an antimicrobial drug-trimethoprim, a food preservative propylgallate and some dyestuffs. Owing to anti-ageing properties, it is quite often used as a constitu- ent of many cosmetic products. It can also protect cells from damage induced by UV-B and ionizing irradiations that cause various skin related diseases [1, 2, 7, 8]. It is also known for its selective cytotoxic nature for cancerous cells and has been found to be negligible or non-toxic for normal cells, suggesting it as a valuable additive with vitamins and as nutritional supplements to prevent the cancer risks [9].

2.SOURCES AND SYNTHETIC PREVIEW OF GAL- LIC ACID
Gallic acid is obtained mainly from tannins either by acid hydrolysis or by enzymatic hydrolysis [8]. Tannins are the

1875-5607/18 $58.00+.00 © 2018 Bentham Science Publishers

fourth most abundant class of constituents of plants which are soluble in polar solvents and are quite distinctive from other polyphenolic compounds by their ability to precipitate proteins. Tannins are alienated into two major groups, proan- thocyanidins (condensed tannins) and polyesters of gallic acid (hydrolysable tannins or hexahydrodiphenic acid) [10]. Various plant parts such as bark, flowers, needles and seeds of vascular plants are the major source of gallic acid. High gallic acid content can be found in gallnuts, grapes, sumac, witch hazel, tea leaves, hops, and oak bark [1-3].
Commercially, gallic acid can be obtained by hydrolyz- ing tannins materials (gallotannins), e.g. pentagalloylglucose (Scheme 1), found in plants, either by chemical hydrolysis or enzymatic hydrolysis. Alternatively, gallic acid can be pro- duced by microbial fermentation (an economical, non- hazardous process) in which the microbial enzyme tannase, obtained mainly either from fungus or bacterium, cleaves the ester bond to release gallic acid molecules. The gallic acid production involving chemicals mainly hot mineral acids or alkalis is economically nonviable because of poor yield and less purity of gallic acid. The process also leads to corrosion of vessels and hence demands more safety precaution [11].

in different neurodegenerative diseases, inflammation, viral infections, autoimmune pathologies and digestive system disorders such as gastrointestinal inflammation and gastric ulcer [13]. Oxidative stress results in the increased genera- tion of superoxide radicals and hydrogen peroxide. The oxygen-related species can also interact in the presence of transition metal catalyst to form many harmful oxidizing species and cause depletion of NADH, GSH and ATP. Thus, such species increase calcium ions inducing cell damage and causing diseases such as atherosclerosis, cancer, and ischaemia [14-17].
Antioxidants are scavengers of free radicals; they reduce or retard free radical generation and prevent the oxidation of cellular oxidizable substrates. It has been observed that gallic acid is a potent antioxidant in emulsion or lipid systems widely used in food packaging, cosmetics and food preserva- tion [18]. At lower concentration, it increases the amount of free radicals and acts as a prooxidant. This activity is attrib- uted to strong reducing power and weak metal chelating abil- ity. Gallic acid acts as an antioxidant at higher concentra- tions due to its scavenging ability [19]. It has been found that the antioxidant ability and water solubility of gallic acid can be increased by conjugation with chitosan. Chitosan possesses antioxidant, anticancerous, anti-inflammatory, antibacterial

G

O
G
O

O
G

O
O

O
G

G

hydolysis

Glucose + 5 Gallic acid
and antihypertensive activities [20]. These properties make it a good candidate for the development of novel drugs. Gallic acid grafted chitosans can interrupt free radical generation and thus act as influential anti-oxidants [21, 22].

G =
Petnagalloylglucose
OH
OH

O OH
Furthermore, it has been observed that the antioxidant activity of gallic acid and its derivatives is also linked to the hydrophobic nature. A hydrophobic antioxidant can easily enter the cytoplasm and prevent ROS formation. Hydropho- bicity was found as an important factor governing the anti- oxidant activity against many models of oxidative stress [23]. However, gallic acid is more hydrophilic than its esters

Scheme (1). Hydrolysis of pentagalloylglucose.

Gallic acid can be formed by the reaction involving 3- dehydroshikimic acid, which involves oxidation and enoliza- tion processes (Scheme 2).

3.MEDICINAL PROPERTIES OF GALLIC ACID
3.1.Antioxidant Activity
Reactive oxygen species (ROS) are generated as a result of inherent oxygen consumption by the cells which leads to oxidative stress. Oxidative stress further leads to various metabolic and chemical changes in biological systems. ROSs not only damage DNA but they also affect DNA messengers causing modulations in DNA replication and cell cycle [12]. It is evident that these free radicals (ROSs) have their roles
and thus it shows weaker antioxidant activity. Other than hydrophobicity, hydroxyl groups especially at the para posi- tion to the carboxylic group maintain the radical scavenging activity in methylated gallic acid derivatives. Steric effects were also found to play a role in the antioxidant activity of esters of gallic acid [24].

3.2.Prevention of DNA from Oxidative Damage
Ferk et al. (2011) studied the DNA shielding properties of gallic acid and reported a reduction of DNA damage (41%) induced by ROS after gallic acid consumption (12.8 mg/person/d for three days) [25]. Gallic acid was also re- ported to increase activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and glutathion- S-transferase with a simultaneous decrease in intracellular

COOH

oxidation NADPH

COOH

oxidation

COOH
H
H

enolization

COOH

HO OH O OH O O HO OH

OH Shikimic acid
OH
3-Dehydorshikimic acid
H OH
OH Gallic acid

Scheme (2). Formation of gallic acid via Shikimic acid pathway.

concentration of ROS in lymphocytes without any alteration in the total antioxidant capacity. It was also found to reduce the oxidative damage of DNA in liver, lymphocytes, colon and lungs and protects these organs from γ-irradiation [25].

3.3.Protection of Hepatocytes Against Oxidative Stress Gallic acid can protect the hepatocytes against oxidative
stress generated by hydrogen peroxide, carbon tetrachloride and treatment with paracetamol. It exhibits potent hepatopro- tective effects due to modulation of antioxidant enzyme ac- tivities, decreasing the malonaldehyde by inhibiting the per- oxidation of lipid. It can reduce the incidence of lesions in liver induced by carbon tetrachloride [26-28]. Peng et al. (2012) reported that gallic acid is safer than ferulic acid and may also be used for treatment of chronic kidney disease (CKD) [29]. Gallic acid grafted chitosans (GA-g-chitosans) can also be used to prevent injury in liver cells due to oxida- tive stress induced by tert-butyl hydroperoxide (t-BHP) [22]. Padma et al. (2011) reported the antioxidant activity of gallic acid against the oxidative stress induced by Lindane, an or- ganochlorine pesticide protecting the rat liver and kidney [30].

3.4.Prevention of Neurodegenerative Diseases
The excellent ability of gallic acid to scavenge free radi- cals and to protect cells against oxidative stress makes it an ideal choice for treating neurodegenerative diseases. It can reduce the incidence of dementia, Alzheimer’s disease, Park- inson’s disease and epilepsy. Mansouri et al. (2013) showed that gallic acid has neuroprotective activity against oxidative stress induced by 6-hydroxydopamine (6-OHDA). Gallic acid increases the passive avoidance memory, non enzymatic and enzymatic antioxidant contents and decreases the amount of malondialdehyde in hippocampus via increasing the cerebral antioxidant defence in the animal model of Park- inson’s disease [31]. Huang et al. (2012) reported that gallic acid shields against neuronal injury induced by kainic acid. It decreases the release of calcium ions, ROS and lipid peroxi- dation and also reduces the increased expression of COX-2 and p38 MAPK (mitogen-activated protein kinases) provid- ing neuroprotective effects against excitotoxins and found application in epilepsy [32]. Cho et al. (2011) studied the effect of gallic acid grafted chitosans on acetylcholinesterase and found that it can inhibit the acetylcholinesterase and elevate the cholinergic transmission. Acetylcholinesterase catalyses the hydrolysis of acetylcholine to choline and ace- tate which results in decreased concentration of cholinergic neurotransmitters leading to Alzheimer’s disease [33].

3.5.Protection of Brain Tissue Against Lead Poisoning Lead toxicity occurs primarily in soft tissues, especially
in the kidneys and the nervous system (CNS) [34]. However, CNS is a primary target for lead toxicity leading to impair- ment of neuromuscular coordination and motor control [35], reduced blood aminolevulinic acid dehydratase (ALA-D) activity and increased brain catalase activity (Table 1). Ex- posure to lead metal also increases brain oxidative stress (OS) estimated by lipid peroxidation (TBARS) and protein carbonyl. Gallic acid has the ability to reverse all these harm-

ful effects of lead poisoning and can also reduce the accumu- lation of lead in brain tissues [19].

3.6.Prevention of Diabetes Mellitus
Diabetes mellitus is a chronic metabolic disorder result- ing hyperglycemia induced by impairment in insulin secre- tion or action. Diabetes mellitus causes derangement in the carbohydrate, lipid and protein metabolism, leading to seri- ous secondary consequences, such as increased in blood glu- cose and glycosylated hemoglobin level, decreased levels of plasma insulin, body weight and total hemoglobin [36]. Oral administration of gallic acid decreases the level of total cho- lesterol, LDL-cholestrol, urea, uric acid, creatinine and in- creases the plasma insulin, C-peptide and glucose tolerance. Gallic acid also restores the total protein, albumin and body weight to near normal. It can also regenerate β-cells of islets and normalizing all the biochemical parameters related to the patho-biochemistry of diabetes mellitus [37, 38].
Diabetes also leads to increase in the level of hepatic and brain lipid peroxidation products, glycoprotein components, lipids and activity of HMG-CoA and decrease in the activi- ties of hepatic and brain antioxidants. Antilipid peroxidative activity of gallic acid reverses the increased level of peroxi- dation to normal level [38-40]. Table 1 shows the effect of gallic acid on various enzymes influenced under disease state.
Kuppan et al., (2010) reported that gallic acid shows a profound effect on the adverse effects of hyperglycemia but it is also capable of attenuating the changes in the gene ex- pression induced by high glucose. Cells treated with high glucose show marked increase in mRNA expression of TNF- α, IL-6, NADPH oxidase and TXNIP, all these increased expressions are attenuated in the presence of gallic acid. High glucose level also results in deficiency of mounting SOCS-3 expression, gallic acid can regulate this effect as well [41] It can also increase insulin secretion in β- cells and can up-regulate mRNA of PDX-1 and insulin. (Saravanan et al., 2010) [42].

3.7.Prevention of Myocardium Infarction and Obesity Coronary atherosclerosis is a chronic disease which may
lead to myocardial infarction, a major cause of death and disability worldwide [43]. Gallic acid can protect the myo- cardium against isoproterenol-induced oxidative stress and bring back the activities of lysosomal enzymes near normal level (Table 1) [44, 45].
Hsu and Yen (2007) studied the effect of gallic acid on the obesity in rats induced by intake of high-fat diet. It re- sulted in decreased body weight, liver weight and peritoneal and epididymal adipose tissues. It also reduces the levels of serum TGA (anti thyroglobulin), phospholipids, cholesterol, insulin and leptin. Increase in glutathione and related en- zymes such as Glutathione peroxidase, Glutathione S- transferase and Glutathione reductase indicates that gallic acid act as a protective compound against endogenous and exogenous toxic substances and free radicals-mediated dam- age in liver tissue as well as in other tissues (Table 1) [46, 47].

Table 1. Effect of gallic acid on various enzymes under pathophysiologic states.

Disease Enzyme Activity in Diseased
State Activity after GA
Treatment Refs.

Lead poisoning ALA-D Catalase Decreases Increases Increases Decreases
[19]

Diabetes mellitus Hepatic hexokinase Glucose-6-phosphatase
Fructose-1,6-bisphosphatase
HMG-CoA reductase Decreases Increases Increases Increases Increases Decreases Decreases Decreases

[37-42]

Myocardium infraction β-glucuronidase
β-Nacetylglucosaminidase
β-galactosidase Cathepsin-B and D
Creatine kinase Creatine kinase-MB,
Aspartate transaminase Aalanine transaminase Lactate dehydrogenase Increases Increase Increases Increases Increases Increases Increases Increases Increases Decreases Decreases Decreases Decreases Decreases Decreases Decreases Decreases Decreases

[44, 45]

Obesity GSH peroxidase GSH reductase
GSH S-transferase Increases Increases Increases Decreases Decreases Decreases
[46]
Oxidative stress induced by 6-OHDA, Parkinson’s disease
Glutathione peroxidase
Decreases
Increases
[31]
Kainic
Acid-Induced Status Epilepticus Mitogen activated protein kinases (MAPK’s)
Rho kinases Increases Increases Decreases No change
[32]
Alzheimer’s disease Acetylcholinesterase Increases Decreases [33]

4.GALLIC ACID AS PRO-OXIDANT
Besides its antioxidant activity, gallic acid is also re- ported to act as pro-oxidant in certain conditions. The pro- oxidant activity is attributed to the production of ROS by gallic acid. Yoshino et al., (2002) reported gallic acid and its alkyl esters induced copper-dependent DNA damage. Reduc- tion of cuprous ions resulted in the formation of 8-hydroxy- 20-deoxyguanosine leading to DNA strand scission [48]. Shinno et al. (2005) investigated in vitro effect of phenolic compounds on the rat liver microsomal glutathione S- transferase (MGST1) and found that gallic acid increased the MGST1 activity through oxidative modification of the en- zyme [49]. Kang et al. (2009) reported that gallic acid de- creased the cell viability of PC12 cells instead of protecting them by hydrogen peroxide oxidative stress [50].

5.ANTICANCER PROPERTIES OF GALLIC ACID Gallic acid and its derivatives have great potential to in-
hibit the migration and invasion of myeloma cells. They can inhibit the cancer cells following different pathways and can regulate the expression of various genes involved in cell cy- cle, metastasis, angiogenesis and apoptosis (Fig. 2). Gallic acid induces apoptosis in various cancer cell lines by dimin-
ishing the activity of anti-apoptotic proteins and increasing the activity of pro-apoptotic proteins. Lazaro et al. (2011) reported that gallic acid induces high levels of topo I and topo II-DNA complexes in cells. These topoisomerase-DNA complexes result in permanent strand break triggering cell death. It has also been reported that pyrogallol moiety of gallic acid induces these complexes by generating hydrogen peroxide [51]. Alkyl esters of gallic acid are more effective against cancer cells as compared to gallic acid. The increased effectiveness of alkyl esters is related to increased hydro- phobicity induced by their side chains [9, 51, 52].

5.1.Prostate Cancer
Prostate cancer is the most invasive and frequently diag- nosed malignancy in males in the USA and is the second leading malignancy in the Western world. The incidence of prostate cancer has steadily increased over the last decade [53]. Veluri et al. (2006) reported the anti-cancer efficacy of grape seed extract against prostate cancer via its anti- proliferative, pro-apoptotic and anti-angiogenic activities [54]. Chen et al. (2009) reported that gallic acid in the leaf extracts of Toona sinensis is cytotoxic to DU145 cells of prostate cancer. Gallic acid inhibits the cell viability of PCA

G2/M phase cell cycle arrest

G0/G1 phase Cell cycle arrest
G1-S phase Cell cycle arrest

p21 and p27

cyclin B1, Cdc2 and Cdc25C ti

ti cyclin D and cyclin E
Cyclin D1, CDK4, Cyclin E, CDK2, and Cyclin A ti

Decreased Inflammation
IL-6, IL-8, COX2,
CXCR4, XIAP, bcl2, VEGF ti

ADAM17 ti
Gallic
Acid

Ribonucleoti de reductase ti

Imbalance d dNTP pool sizes

Glutathione ti, ROSti
Bax ti , Bcl-Xl ti

caspase3,

PI3K/Akt and Ras/MAPK signaling pathway inactivated
caspase9 and PARPti

Apoptosis

Fig. (2). Diagrammatic representation of different effects of gallic acid on oncogenic pathways.

Apoptosis

by inducing cell shrinkage and apoptotic vacuole display. They also reported that gallic acid causes DNA double strand breaks, leading to increased tail moment, indicating the cells at apoptotic stages. Gallic acid reduces the level of Bcl-xL (anti-apoptotic protein) and increases the Bax protein (pro- apoptotic) [55]. In addition, Chen et al. (2009) also reported that gallic acid arrests cancer cells at G2/M phase by down-regulating the expression of cyclin B1, Cdc2 and Cdc25C and increasing the levels of p-Cdc2(Try15), p- Cdc5C(ser216), p-Chk1(ser345) and p-Chk2(ser516) [55].

5.2.Leukemia
Isuzugawa et al. (2001) reported that gallic acid and its derivatives can induce Ca2+ ions dependent apoptosis in leu- kemia cells [56]. In addition, gallic acid inhibits superoxide dismutase, ribonucleotide reductase, leading to an imbal- anced dNTP pool sizes and cyclooxygenases (linked to re-

duced cancer risk in multiple tissues) during apoptosis in HL-60 leukemia cells [57, 58]. Huang et al., (2012) studied the effect of gallic acid on the tumor regression in vitro cell cultures from Toona sinensis (TS) leaf extracts and in vivo athymic nude mice. TS leaf extracts reduce the levels of Cy- clin D1, CDK4, Cyclin E, CDK2, and Cyclin A, arresting the HL-60 cells at G1-S transition phase. It also modulates the tumor progression in xenograft tumors [59]. Reddy et al., (2012) investigated the cytotoxic activity of gallic acid on chronic myeloid leukemia (CML) cell line-K562 and re- ported that gallic acid reduces the cell viability of K562 cells by increasing the level p21 and p27 and inhibiting the levels of cyclin D and cyclin E leading to G0/G1phase arrest. Apoptotic activity induced by gallic acid on K562 cells lines involves death receptor and mitochondrial-mediated path- ways by inhibiting BCR/ABL kinase, NF-β activity and COX-2 [60].

5.3.Breast Cancer
Breast cancer is the most prevalent cancer among women leading to death worldwide. Many hormone therapies are used to treat breast cancer but these therapies are facing the problem of resistance. Hwang et al (2008) suggested that gallic acid inhibits the proliferation of MCF-7 human breast cancer cells by decreasing the specificity of UDP-glucose dehydrogenase that is up-regulated in breast cancer cells as a response to elevated androgen [61]. García-Rivera et al. (2011) reported that Vimang, a standardized extract derived from Mango bark (Mangifera Indica L.), contains glucosylxanthone mangiferin and indanone gallic acid. Both the constituents of vimang shows anti-tumor activity against highly aggressive and metastatic breast cancer cell type MDA-MB231 by inhibiting the classical activation of NF-κB by IKKα/β kinases, resulting into impaired degradation of IκB, NFκB translocation and NFκB/DNA binding. Gallic acid also inhibits additional NFκB pathways such as MEK1, JNK1/2 and p90RSK involved in the survival of cancer cells and therapy resistance. In combination to these effects, it also inhibits the NFκB target genes like, IL-6, IL-8, COX2, CXCR4, XIAP, bcl2, VEGF involved in various processes including inflammation, metastasis, anti-apoptosis and angi- ogenesis [62] (Table 2).

5.4.Brain Tumor
Lu et al. (2010) reported that gallic acid can function as a valuable candidate for the treatment of brain tumor. Gallic acid reduced the cell viability and proliferation of U87 and U251 cells. However, it also reduces the cell viability of normal brain endothelial cells but in a much lower amount. Gallic acid also inhibits the migration and invasion of glioma by downregulating the ADAM17 resulting into inactivation of PI3K/Akt and Ras/MAPK signaling pathway. Brain tumor results into tube formation in the cells by inducing extensive neovascularization in adjacent tissues. Gallic acid is reported to inhibit tube elongation [63, 64].

5.5.Gastric Cancer
Ho et al., (2010, 2013) showed that gallic acid is cyto- toxic to gastric adenocarcinoma cells (AGS). Gallic acid inhibits the migration and invasion of AGS cells by inhibit- ing the activity of NF-κB and down-regulation of PI3 K/AKT pathway [65, 66]. Gallic acid reduces the activity of proteolytic enzymes including matrix metalloproteinases like MMP-2 and MMP-9 which in overexpressed state is respon- sible for metastasis of cancerous cells and also reduces the levels of Ras, cdc42, Rac1 and RhoA but increases the activ- ity of antitumor protein RhoB in a dose-dependent manner [67].

5.6.Cervical Cancer
You et al. (2010) reported that gallic acid inhibits the cell growth of HeLa and human umbilical vein endothelial cells accompanied by loss in the mitochondrial membrane poten- tial, glutathione depletion and increase in the ROS [68]. Zhao and Hu (2013) reported that gallic acid decreased the invasion of HeLa and HTB-35 cells invitro. They also

showed that gallic acid may also contribute in the suppres- sion of cancer progression by inhibiting various growth fac- tors and kinases signaling pathways [69].

5.7.Lung Cancer
You and Park (2010) reported that gallic acid inhibits the growth of Calu-6 and A549 lung cancer cells. The cell death is accompanied by a loss of mitochondrial membrane poten- tial along with an increase in ROS level and a decrease in glutathione [70]. Choi et al. (2009) showed that gallic acid from Rosa rugosa acts as an inhibitor of histone acetyltrans- ferase (HAT). It also inhibits p300-induced p65 acetylation in vitro as well as in vivo, increases the level of cytosolic IκBα, prevents lipopolysaccharide (LPS) induced p65 trans- location to the nucleus, and suppresses LPS-induced nuclear factor-κB activation in A549 lung cancer cell [71].

5.8.Colon Cancer
Colon cancer is a multifactorial disease linked to diet [72]. 1,2 Dimethylhydrazine (DMH) induces the formation of methyl adducts leading to genetic mutations and altered gene transcription [73]. DMH exerts carcinogenic effects after activation by phase I and phase II xenobiotic- metabolizing enzymes [74]. In DMH induced rats, the activity of phase II enzyme decreases while the activity of phase I enzymes increases. Gallic acid supplementation was reported to revert the effect of DMH by decreasing the activ- ity of phase I enzymes and increase in the activity of phase II enzymes [75]. Subramanian et al. (2016) reported that gallic acid has time-dependent inhibitory effect on HCT-15 colon cancer cells. They also showed that gallic acid induced the ROS dependent apoptosis and inhibited the growth of colon cancerous cells [76].

5.9.Osteosarcoma
Osteosarcome is a highly malignant bone cancer in chil- dren and adolescents, characterized by the formation of neo- plastic bone tissue [77, 78]. Liao et al. (2012) suggested that gallic acid inhibits the migration and invasion of human os- teosarcoma U-2 OS cells, decreases the protein levels of growth factor receptor-bound protein 2(GRB2), c-Jun N- terminal kinase (JNK), IκB kinase (IKK), mitogen-activated protein kinase (MAPK), matrix metalloproteinases(MMPs), phosphoinositide 3-kinase(PI3K), protein kinase C (PKC), RAC-alpha serine/threonine-protein kinase (AKT/PKB) and extracellular signal-regulated kinase 1/2 (ERK1/2) [79].

6.ANTI-INFLAMMATORY ACTIVITY OF GALLIC ACID
Proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and vascular endothelial growth factor (VEGF) play a vital role in inflammation. A number of biological agents have been developed to treat inflammation, including agents that reduce the activity of specific cytokines or their receptors (anti-cytokine therapies), block lymphocyte trafficking into tissues, prevent the bind- ing of monocyte-lymphocyte costimulatory molecules, or deplete B lymphocytes [80]. Chen et al. (2014) reported that gallic acid has a significant role in the treatment of endo-

Table 2. Effect of gallic acid on different cancer cell lines.

Cancer Type of Cell Effect of Gallic Acid IC50 Refs.

Leukemia HL-60
K567 Apoptosis Apoptosis 24mM 33 µM [59]
[60]
Prostate cancer DU-145 Apoptosis 15.6 µg/mL [55]

Breast cancer MCF-7 MDA-MB231 Antiproliferative Apoptosis
10 µg/ml [61]
[62]

Brain tumor U87
U251n Apoptosis Apoptosis
[63]
Gastric cancer AGS Anti-metastasis 0.01 mM [65]
Cervical cancer HeLa Apoptosis 80 µM [68]

Lung cancer Calu-6 A549 Apoptosis Apoptosis 10-50 µM 100-200 µM [69]
[70]
Osteosarcoma U-2 OS Anti-metastatic - [77]
Colon cancer Caco2 Apoptosis - [62]
Fibrosarcoma HT1080 Apoptosis - [62]

toxemia as it had an antagonistic role to the inflammatory cytokines IL-10, IL-1β and TNF-α in serum. Kim et al. (2005) found that gallic acid had an inhibitory effect on the pro-inflammatory cytokine, NF B and the inhibition was found to be p38 mitogen-activated protein kinase dependent. Also, gallic acid was found to inhibit systemic and IgE me- diated allergic reaction. Gallic acid actually inhibited mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression [81, 82].
Recently gallic acid and its derivatives have been re- ported as an excellent anti inflammatory agents. Sanae et al. (2003) examined the vascular effect of gallic acid on rat tho- racic aorta and suggested that gallic acid induced endothe- lium-dependent contraction and inhibit the endothelium- dependent relaxation. It was shown to exert a contractile effect on phenylephrine precontracted endothelium intact arteries. Gallic acid treatment can also attenuate the acetylcholine-induced relaxation and reduces sodium nitro- prusside potency in relaxation. Gallic acid induces all these effects on the contraction and relaxation of arteries, probably through inhibition of endothelial nitric oxide. As nitric oxide plays an important role in allergic responses, it indicates that gallic acid can act as a potent anti-inflammatory agent [83].
Mast cells are mediators of immediate hypersensitive allergic reactions, their action includes the release of hista- mine and is mediated by IgE. Kim et al. (2006) reported that gallic acid can inhibit the inflammatory responses derived from mast cells by inhibiting the release of IgE induced his- tamine. This inhibitory effect of gallic acid is a result of modulated cAMP and intracellular calcium ions. They also reported that gallic acid has nuclear factor κB and p38 mito- gen-activated protein kinase-dependent inhibitory effects on
pro-inflammatory reactions, leading to decreased phorbol 12- myristate 13-acetate plus calcium ionophore A23187- stimulated pro-inflammatory cytokine gene expression and production such as TNF-a and IL-6 in human mast cells [84].
Das et al., (2011) reported that gallic acid in Terminalia chebula extract inhibits the nuclear factor- κB in human lym- phoblastic T (Jurkat) cells. Gallic acid also down-regulate some genes such as IL 8 and MCP 1, regulated by nuclear factor- κB [85]. Hsiang et al., (2013), investigated the anti- inflammatory effects of gallic acid in the leaf of Toona sinensis, is mediated by inhibiting the nuclear factor-κB pathway [86]. Liu et al. (2013) elucidated the gallic acid as potential anti-allergic and anti-inflammatory agent by studying its effect on human basophile cells, (KU812 cells), which are crucial in allergic inflammation. Gallic acid de- creases the activation of intracellular signaling molecule p38 mitogen-activated protein kinase, NF-B and c- Jun amino- terminal kinase induced by IL-33. Gallic acid significantly suppresses the expression of intracellular adhesion molecules ICAM-1, IL-6 and chemokines CCL2, CCL5 and CXCL8 [87]. Yoon et al., (2013), elucidated gallic acid as a potent therapeutic agent for rheumatoid arthritis. They investigated the pro-apoptotic and anti-inflammatory effects of gallic acid on fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and reported that 10 or more µM of gallic acid decreases the cell viability. A lower dose of gallic acid increases the activity of caspase-3 and regulated the production of Bcl-2, Bax, p53 and pAkt [88]. Gallic acid derivatives also contain the anti-inflammatory activity, as reported by Lin and Lin (1997) Epigallocatechin-3-Gallate decreases the expression of the transcription factor, NF-κB leading to inhibition of LPS-induced inducible nitric-oxide

synthase gene expression in mouse peritoneal macrophages [89]. Yang et al., (1998) proposed a possible mechanism for the anti-inflammatory activity of gallic acid derivative, Epi- gallocatechin-3-Gallate (ECGC). They reported that EGCG decreases TNF-α production induced by LPS in the macro- phage cell line RAW264.7 and peritoneal macrophages by blocking NF-κB activation [90]. Yang et al., (2001) eluci- dated that EGCG inhibits the IκB kinase complex (IKK) activity leading to the decreased activity of the transcription factor nuclear factor-κB. They also reported that gallate group is essential for activity [91]. Thanh-Sang et al. (2012) reported that treatment with Gallic acid-grafted chitooligo- saccharides results into a remarkable blockade in the degradation of inhibitory κB-α (IκB-α) protein, translocation of NF-κB, and phosphorylation of mitogen-activated protein kinases (MAPKs) in RBL-2H3 mast cells. Gallic acid onto chitooligosaccharides (G-COS) was suggested as a promis- ing candidate for treating anti-allergic reactions [92]. Hyung et al.,(2006) showed that ECGC inhibits the signaling path- ways ( MyD88 and TRIF) of toll-like receptors (TLRs) that play essential role in the induction of innate immunity [93].

7.ANTI-MICROBIAL ACTIVITY
Gallic acid is one of the most biologically active phenolic compounds of plant origin. It has been shown to possess a broad range of antimicrobial activity including human patho- gens (Staphylococcus aureus, Corynobacterium accolans), a plant pathogen (Erwinia carotovora) and human pathogenic yeast (Candida albicans) [94].
Meshram et al. (2011) reported that acetone extract of Terminalia bellerica, containing gallic acid is a glycoamylase inhibitor and has a significant antimicrobial activity against E.coli, B. subtilis and S. Aureus but a lower activity on P. Aeurogenosa [95]. Borges et al. (2013) assessed the anti- microbial action and mechanism of action of gallic acid. They showed that gallic acid changes the membrane poten- tial and inhibits the activity of Escherichia coli, Pseudo- monas aeruginosa, Staphylococcus aureus, and Listeria monocytogenes. [96]. Kang et al. (2008) reported that gallic acid and methyl gallate inhibit the proliferation of oral bacte- ria and formation of Streptococcus mutans biofilms [97]. Lee and Je (2013) showed that gallic acid grafted chitosans in- hibit the activity of foodborne pathogens by disrupting the cell membrane [98]. Shibata et al. (2005) elucidated that ethyl gallate isolated from a dried pod of Caesalpinia spinosa increases the susceptibility of methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus towards β- lactams. They also demonstrated that the modifi- cation in the chain length modifies the activities of methyl gallates and 1-nonyl and 1-decyl gallate which increases the activity of gallates [99]. Rangel et al. (2010) suggested that gallic acid ester derivatives can inhibit the ABC transporter Pdr5p in Saccharomyces cerevisiae. The Pdr5p transporter confers the multidrug resistance in S. cerevisiae. They sug- gested that ester derivatives with longer side chains (8-16 carbon) and derivatives with side chains of 8-12 carbons that retained hydroxyl groups on the benzene ring are potent in- hibitors of Pdr5p ATPase [100].

Gallic acid and its ester derivatives are also known in- hibitors of viruses. Choi et al. (2010) reported that gallic acid inhibits the replication of Human rhinoviruses-2 (HRV-2) and HRV-3 by its antioxidant activity [101]. Kratz et al. (2008) showed the anti-Herpes Simplex Virus-1( HSV-1) and anti HIV-1 (Human immunodeficiency virus-1) activity of gallic acid and Pentyl Gallate. They reported that anti-HSV- 1 activity is mainly mediated by inhibition of replication and virucidal properties [102]. Barardi et al.(2008) reported that gallic acid and Pentyl Gallate can inhibit HSV-2. Gallic acid and Pentyl Gallate inhibit the attachment of virus particles to the cells and its subsequent cell-to-cell spread activity [103]. Nutana et al. (2013) elucidated that Ellagic acid & gallic acid from Lagerstroemia speciosa L. can inhibit the HIV-1 by inhibiting the activity of HIV protease and reverse tran- scriptase respectively [104].

8.MISCELLANEOUS
Hamamura et al., (1966) elucidated that Gallic acid pro- motes the growth in silkworm larvae [105]. Chandra et al., (2004) reported that reaction of gallic acid with laccase in the presence of a high-κ (91) kraft pulp results into a modi- fied and improved pulp. The pulp showed 34%, 20%, and 72% improvements in burst, tensile, and wet tensile strength respectively due to improved hydrogen bonding between fibers and creation of phenoxy radical cross-links within the sheet [106]. Jung et al., (2010) reported that gallic acid and linoleic acid mixture can improve the antioxidant potential and nutritional and functional qualities of broiler breast meat [107]. Gallic acid at 1 mm concentration level was found to have a pronounced effect on blood vessel formation, inhibit- ing angiogenesis strongly [54]. Jeon et al., (2010) reported that combination of gallic acid and syringic acid catalyzed by laccase leads to polymerization and development of brown colored hair dye [108]. Jung et al., (2011) reported that a mixture of gallic acid and linoleic acid can improve the anti- oxidant activity and quality of fatty acids in the egg yolk and it also reduces the level of cholesterol [109]. Neo et al., (2013) showed that gallic acid loaded zein (Ze-GA) electros- pun fiber mats have the antibacterial activity and can be used as packaging material in the food industry [110]. Ghosh and Pal (2013) reported that gallic acid can protect the cells of Salmonella typhimurium from harmful radiations. The pro- tective ability is due to its radical scavenging activity and it can inhibit or reverse the formation of dimmers in DNA [111]. Khatkar et al., (2013) reported that amide, ester and anilide derivatives of gallic acid can be used in pharmaceuti- cal preparations. These derivatives can inhibit the activity of E.coli, S. aureus, C. albicans, B.subtilis and A. niger in the preparation of aluminium hydroxide gel-USP (antacid) [112].

CONCLUSION
Gallic acid seems to have broad-spectrum therapeutic properties including anti-fungal, antioxidant and anti-viral activities. The selective cytotoxicity of this key molecule against cancer cells only is extremely important for its wide spectrum role as an anticancer which needs to be explored further to derive its full potential. Gallic acid is also attrib-

uted to possess antidiabetic potential and can be successfully employed to treat albuminuria as well. Almost all plants have been known to possess this key molecule having more abundance in grapes, tea, hops and oak bark where it occurs either as a free molecule or as part of a tannin molecule. Keeping in view of its widespread occurrence, Gallic acid and its derivatives, therefore could be further developed as promising lead molecules for novel drug development cater- ing to the needs of industrial and pharmaceutical sectors.

CONSENT FOR PUBLICATION
Not applicable.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS
Declared none.

REFERENCES
[1]Thompson, M.A.; Collins, P.B. Handbook on Gallic Acid: Natural Occurrences, Antioxidant Properties and Health Implications, Nova Science Publishers Inc, United States, 2013.
[2]Ahmed, E.F.; Mohamed, T.; Ju, Y. Iron Complexation Studies of Gallic Acid. J. Chem. Eng. Data, 2009, 54, 35-42.
[3]Werner, R.A.; Rossmann, A.; Schwarz, C.; Bacher, A.; Schmidt, H.L.; Eisenreich, W. Biosynthesis of gallic acid in Rhus typhina: Discrimination between alternative pathways from natural oxygen isotope abundance. Phytochemistry, 2004, 65, 2809-2813.
[4]Rajalakshmi, K.; Devaraj, H.; Devaraj, S. Assessment of the no- observed-adverse-effect level (NOAEL) of gallic acid in mice. Food Chem. Toxi., 2001, 39, 919-922.
[5]O’Neil M.J; Smith A; Heckelman P.E; Obenchain J.R; Gallipeau J.A.R; D’Arecca M.A; eds. Gallic acid. In: The Merck index 13th ed. Merck research laboratories, NJ, 2001, pp 261.
[6]Phaechamud, T.; Yodkhum, K., Characteristic of hydroxypropyl methyl cellulose gel comprising gallic acid dispersed in N-methyl pyrrolidone. Res. J. Pharm. Biol. Chem. Sci., 2012, 3(1), 975-8585.
[7]Phiriyawirut, M.; Phachamud, T. Suitable Electrospinning Condi- tion for Gallic Acid-loaded Cellulose Acetate Fiber. Res. J. Pharm. Biol. Chem. Sci., 2011, 2(3), 975-8585.
[8]Beniwal, V.; Kumar, A.; Sharma, J.; Chhokar, V. Recent advances in industrial application of tannases: A review. Rec. Pat. Biotech- nol., 2013, 7(3), 228-233.
[9]Verma, S.; Singh, A.; Mishra, A. Gallic acid: Molecular rival of cancer. Environ. Toxicol. Pharmacol., 2013, 3(5), 473-485.
[10]Silanikove, N.; Perevolotsky, A.; Provenza, F.D. Use of tannin- binding chemicals to assay for tannins and their negative postinges- tive effects in ruminants. Anim. Feed Sci. Tech., 2001, 91(1), 69-81.
[11]Dewick, P.M. Medicinal Natural Products. John Wiley＆Sons Ltd., 2002, 121-166.
[12]Hu, J.J.; Dubin, N.; Kurland, D.; Ma, B.L.; Roush, G.C. The effects of hydrogen peroxide on DNA repair activities. Mutat. Res. DNA Repair, 1995, 336, 193-201.
[13]Subhashini, N.; Thangathirupathi, A; Lavanya, N. Antioxidant activity of Trigonella foenum graecum using various in vitro and ex vivo models. Int. J. Pharm. Sci., 2011, 3, 96-102.
[14]Yen, G.C.; Duh, P. D.; Tsai, H.L. Antioxidant and pro-oxidant properties of ascorbic acid and gallic acid. Food Chem., 2002, 79, 307-313.
[15]Pasanphan, W.; Chirachanchai, S. Conjugation of gallic acid onto chitosan: An approach for green and water-based antioxidant. Carb. Pol., 2008, 72, 169-177.
[16]Bhadoriya, U.; Sharma, P.; Solanki, S.S. In vitro free radical scav- enging activity of gallic acid isolated from caesalpinia decapetala wood. Asian Pac. J. Trop. Dis., 2012, S833-S836.

[17]Smith, C.; Halliwell, B.; Aruoma, O.I. Protection by albumin against the pro-oxidant actions of phenolic dietary components. Food Chem. Toxicol., 1992, 30, 483-489.
[18]Madsen, H.L.; Bertelsen, G. Spices as antioxidants. Trends Food Sci. Tech., 1995, 6(8), 271-277.
[19]Reckziegel, P.; Dias, V.T.; Benvegnú, D.; Boufleur, N.; Barcelos, R.C.S.; Segat, H.J.; Pase, C. S.; Santos, C.M.M.; Flores, É.M.M.; Bürger, M.E. Locomotor damage and brain oxidative stress in- duced by lead exposure are attenuated by gallic acid treatment. Tox. Let., 2011, 203, 74-81.
[20]Aruoma, O.I.; Murcia, A.; Butler, J.; Halliwellt, B. Evaluation of the antioxidant and prooxidant actions of gallic acid and its deriva- tives. J. Agric. Food Chem., 1993, 41, 1880-1885.
[21]Cho, Y.S.; Kim, S.K.; Ahn, C.B.; Je, J.Y. Preparation, characteriza- tion, and antioxidant properties of gallic acid-grafted-chitosans. Carbohydr. Polym., 2011, 83, 1617-1622.
[22]Senevirathne, M.; Jeon, Y.J.; Kim, Y.T.; Park, P.J.; Jung, W.K.; Ahn, C.B.; Je, J.Y. Prevention of oxidative stress in Chang liver cells by gallic acid-grafted-chitosans. Carbohydr. Polym., 2012, 87, 876-880.
[23]Ishige, K.; Chen, Q.; Sagara, Y.; Schubert, D. The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death. J. Neurosci., 2001, 21(16), 6069-6076.
[24]Lu, Z.; Nie, G.; Belton, P.S.; Tang, H.; Zhao, B. Structure-activity relationship analysis of antioxidant ability and neuroprotective ef- fect of gallic acid derivatives. Neurochem. Intl., 2006, 48, 263-274.
[25]Ferk, F.; Chakraborty, A.; Jäger, W.; Kundi, M.; Bichler, J.; Misík, M.; Wagner, K.; Grasl-Kraupp, B.; Sagmeister, S.; Haidinger, G.; Hoelzl, C.; Nersesyan, A.; Dusinská, M.; Simic, T.; Knasmüller, S. Potent protection of gallic acid against DNA oxidation: Results of human and animal experiments. Mutat. Res., 2011, 715, 61-71.
[26]Li, T.; Zhang, X.; Zhao, X. Powerful protective effects of gallic acid and tea polyphenols on human hepatocytes injury induced by hydrogen peroxide or carbon tetrachloride in vitro. J. Med. Plant. Res., 2010, 4(3), 247-254.
[27]Tung, Y.T.; Wu, J.H.; Huang, C.C.; Peng, H.C.; Chen, Y.L.; Yang, S.C.; Chang, S.T. Protective effect of Acacia confusa bark extract and its active compound gallic acid against carbon tetrachloride- induced chronic liver injury in rats. Food Chem. Tox., 2009, 47, 1385-1392.
[28]Rasool, M.K.; Sabina, E.P.; Ramya, S.R.; Preety, P.; Patel, S.; Mandal, N.; Mishra, P.P.; Samuel, J. Hepatoprotective and antioxi- dant effects of gallic acid in paracetamol-induced liver damage in mice. J. Pharm. Pharmacol., 2010, 62, 638-643.
[29]Peng, C.C.; Hsieh, C.L.; Wang, H.E.; Chung, J.Y.; Chen, K.C.; Peng, R.Y. Ferulic acid is nephrodamaging while gallic acid is re- nal protective in long term treatment of chronic kidney disease. Clin. Nutr., 2012, 31, 405-414.
[30]Padma, V.V.; Sowmya, P.; Felix, T.A.; Baskaran, R.; Poornima, P. Protective effect of gallic acid against lindane induced toxicity in experimental rats. Food Chem. Tox., 2011, 49, 991-998.
[31]Mansouri, M.T.; Farbood, Y.; Sameri, M.J.; Sarkaki, A.; Naghi- zadeh, B.; Rafeirad, M. Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chem., 2013, 138, 1028-1033.
[32]Huang, H.L.; Lin, C.C.; Jeng, K.C.G.; Yao, P.W.; Chuang, L.T.; Kuo, S.L.; Hou, C.W. Fresh green tea and gallic acid ameliorate oxidative stress in kainic acid-induced status epilepticus. J. Agric. Food Chem., 2012, 60, 2328-2336.
[33]Cho, Y.S.; Kim, S.K.; Ahn, C.B.; Je, J.Y. Inhibition of acetylcho- linesterase by gallicacid-grafted-chitosans. Carbohyd. Polym., 2011, 84, 690-693.
[34]Todd, A.C.; Wetmur, J.G.; Moline, J.M.; Godbold, J.H.; Levin, S.M.; Landrigan, P.J. Unraveling the chronic toxicity of lead: An essential priority for environmental health. Environ. Health Per- spect., 1996, 104(1), 141-146.
[35]Schwartz, B.S.; Chen, S.; Caffo, B.; Stewart, W.F.; Bolla, K.I.; Yousem, D.; Davatzikos, C. Relations of brain volumes with cogni- tive function in males 45 years and older with past Pb exposure. Neuroimage, 2007, 37(2), 633-641.
[36]Anderson, R.A.; Cheng, N.; Bryden, N.A.; Polansky, M.M.; Cheng, N.; Chi, J.; Feng, J. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes, 1997, 46(11), 1786-1791.

[37]Latha, R.C.R.; Daisy, P. Insulin-secretagogue, antihyperlipidemic and other protective effects of gallic acid isolated from Terminalia bellerica Roxb. in streptozotocin-induced diabetic rats. Chem. Bio. Intl., 2011, 189, 112-118.
[38]Punithavathi, V.R.; Prince, P.S.M.; Kumar, R.; Selvakumari, J. Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats. Eur. J. Pharmacol., 2011, 650, 465-471.
[39]Prince, P.S.M.; Kumar, M.R.; Selvakumari, C.J. Effects of gallic acid on brain lipid peroxide and lipid metabolism in streptozotocin- induced diabetic wistar rats. J. Biochem. Mol. Toxicol., 2011, 25(2), 101-107.
[40]Punithavathi, V.R.; Prince, P.S.M.; Kumar, M.R.; Selvakumari, C.J. Protective effects of gallic acid on hepatic lipid peroxide me- tabolism, glycoprotein components and lipids in streptozotocin- induced type ii diabetic wistar rats. J. Biochem. Mol. Toxicol., 2011, 25(2), 68-76.
[41]Kuppan, G.; Balasubramanyam, J.; Monickaraj, F.; Srinivasan, G.; Mohan, V.; Balasubramanyam, M. Transcriptional regulation of cytokines and oxidative stress by gallic acid in human THP-1 monocytes. Cytokine, 2010, 49, 229-234.
[42]Sameermahmood, Z.; Raji, L.; Saravanan, T.; Vaidya, A.; Mohan, V.; Balasubramanyam, M. Gallic acid Protects RINm5F b-cells from glucolipotoxicity by its antiapoptotic and insulin-secretagogue actions. Phytother. Res., 2010, 24, S83-S94.
[43]Thygesen, K.; Alpert, J.S.; White, H.D. Universal definition of myocardial infarction. J. Am. Coll. Cardiol., 2007, 50(22), 2173- 2195.
[44]Priscilla, D.H.; Prince, P.S.M. Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial in- farction in wistar rats. Chem. Bio. Interact., 2009, 179, 118-124.
[45]Prince, P.S.M.; Priscilla, H.; Devika, P.T. Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats. Eur. J. Pharmacol., 2009, 139, 139-143.
[46]Hsu, C.L.; Yen, G.C. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br. J. Nutr., 2007, 98, 727-735.
[47]Czeczot, H.; Ścibior, D.; Skrzycki, M.; Podsiad, M. Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma. Acta Biochi. Pol., 2006, 53(1), 237-241.
[48]Yoshino, M., Haneda, M., Naruse, M., Htay, H.H., Iwata, S., Tsub- ouchi, R., and Murakami, K. Prooxidant action of gallic acid com- pounds: Copper-dependent strand breaks and the formation of 8- hydroxy-20-deoxyguanosine in DNA. Toxicol. In Vitro, 2002, 16, 705-709.
[49]Shinno, E.; Shimoji, M.; Imaizumi, N.; Kinoshita, S.; Sunakawa, H.; Aniya, Y. Activation of rat liver microsomal glutathione S- transferase by gallic acid. Life Sci., 2005, 78, 99-106.
[50]Kang, M.K.; Kang, N.J.; Jang, Y.J.; Lee, K.W.; Lee, H.J. Gallic acid induces neuronal cell death through activation of c-jun n- terminal kinase and downregulation of Bcl-2, natural compounds and their role in apoptotic cell signaling pathways. Ann. N.Y. Acad. Sci., 2009, 1171, 514-520.
[51]Lazaro, M.L.; Manuel J.M.C.; Moron, E.B.; Austin, C.A. Green tea constituents (2)-epigallocatechin-3-gallate (EGCG) and gallic acid induce topoisomerase I- and topoisomerase II-DNA complexes in cells mediated by pyrogallol-induced hydrogen peroxide. Mutage- nesis, 2011, 26(4), 489-498.
[52]Locatelli, C.; Filippin-Monteiro, F.B.; Pasa, T.B.C. Alkyl esters of gallic acid as anticancer agents: A review. Eur. J. Med. Chem., 2013, 60, 233-239.
[53]Stangelberger, A.; Waldert, M.; Djavan, B. Prostate cancer in eld- erly men. Rev. Urol., 2008, 10(2), 111-119.
[54]Veluri, R.; Singh, R.P.; Liu, Z.; Thompson, J.A.; Agarwal, R.; Agarwal, C. Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. Carcinogenesis, 2006, 27(7), 1445-1453.
[55]Chen, H.M.; Wu, Y.C.; Chia, Y.C.; Chang, F.R.; Hsu, H.K.; Hsieh, Y.C.; Chen, C.C.; Yuan, S.S. Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS-mediated anti-cancer activity in human prostate cancer cells. Cancer Lett., 2009, 286, 161-171.

[56]Isuzugawa, K.; Inoue, M.; Ogihara, Y. Ca2-dependent caspase activation by gallic acid derivatives. Biol. Pharm. Bull., 2001, 24, 844-847.
[57]Zhang, W.; Hashimoto, K.; Yu, G.Y.; Sakagami, H. Decline of superoxide dismutase activity during antioxidant-induced apoptosis in HL-60 cells. Anticancer Res., 2002, 22, 219-224.
[58]Madlener, S.; Illmer, C.; Horvath, Z.; Saiko, P.; Losert, A.; Herba- cek, I.; Grusch, M.; Elford, H.L.; Krupitza, G.; Bernhaus, A.; Frit- zer-Szekeres, M.; Szekeres, T. Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells. Cancer Lett., 2007, 245, 156-162.
[59]Huang, P.; Hseu, Y.; Lee, M.; Kumar, K.J.S.; Wu, C.; Hsu, L.; Liao, J.; Cheng, I.; Kuo, Y.; Huang, S.; Yang, H. In vitro and in vivo activity of gallic acid and Toona sinensis leaf extracts against HL-60 human premyelocytic leukemia. Food Chem. Toxicol., 2012, 50, 3489-3497.
[60]Reddy, T.C.; Reddy, D.B.; Aparna, A.; Arunasree, K.M.; Gupta, Geetika.; Achari, C.; Reddy, G.V.; Lakshmipathi, V.; Subra- manyam, A.; Reddanna, P. Anti-leukemic effects of gallic acid on human leukemia K562 cells: Downregulation of COX-2, inhibition of BCR/ABL kinase and NF-jB inactivation. Toxicol. in vitro, 2012, 26, 396-405.
[61]Hwang, E.Y.; Huh, J.; Choi, M.; Choi, S.Y.; Hong, H.; Cho, S. Inhibitory effects of gallic acid and quercetin on UDP-glucose de- hydrogenase activity. FEBS J., 2008, 582, 3793-3797.
[62]García-Rivera, D.; Delgado, R.; Bougarne, N.; Haegeman, G.; Vanden Berghe, W. Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells. Cancer Lett., 2011, 305, 21-31.
[63]Lu, Y.; Jiang, F.; Jiang, H.; Wu, K.; Zheng, X.; Cai, Y.; Katak- owski, M.; Chopp, M.; Tony, S. Gallic acid suppresses cell viabil- ity, proliferation, invasion and angiogenesis in human glioma cells. Eur. J. Pharmacol., 2010, 641, 102-107.
[64]Prados, M.D.; Levin, V. Biology and treatment of malignant glioma. Semin. Oncol., 2000, 27, 1-10.
[65]Ho, H.; Chang, C.; Ho, W.; Liao, S.; Wu, C.; Wang, C. Anti- metastasis effects of gallic acid on gastric cancer cells involves in- hibition of NF-jB activity and downregulation of PI3K/AKT/small GTPase signals. Food Chem. Tox., 2010, 48, 2508-2516.
[66]Ho, H.; Chang, C.; Ho, W.; Liao, S.; Lin, W.; Wang, C. Gallic acid inhibits gastric cancer cells metastasis and invasive growth via in- creased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-κB activity. Toxicol. Appl. Pharm., 2013, 266, 76-85.
[67]Kleiner, D.E., Stetler-Stevenson, W.G. Stetler-Stevenson. Matrix metalloproteinases and metastasis. Cancer Chemother. Pharmacol., 1999, 3(1), S42-S51.
[68]You, B.R.; Moon, H.J.; Han, Y.H.; Park, W.H. Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or ne- crosis. Food Chem. Tox., 2010, 48, 1334-1340.
[69]Zhao, B.; Hu, M. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells. Oncol. Lett., 2013, 6(6), 1749-1755.
[70]You, B.R.; Park, W.H. Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase. Toxicol. in vitro, 2010, 24, 1356-1362.
[71]Choi, K.; Lee, Y.; Jung, M.G.; Kwon, S.H.; Kim, M.; Jun, W. J.; Lee, J.; Lee, J.M.; Yoon, H. Gallic acid suppresses lipopolysaccha- ride -induced nuclear factor-κB signaling by preventing rela acety- lation in a549 lung cancer cells. Mol. Cancer Res., 2009, 7(12), 2011-2021.
[72]Lipkin, M.; Reddy, B.; Newmark, H.; Lamprecht, S.A. Dietary factors in human colorectal cancer. Ann. Rev. Nutr., 1999, 19(1), 545-586.
[73]Choudhary, G.; Hansen, H. Human health perspective of environ- mental exposure to hydrazines: A review. Chemosphere, 1998, 37(5), 801-843.
[74]Sheweita, S.A.; Tilmisany, A.K. Cancer and phase II drug- metabolizing enzymes. Curr. Drug Metab., 2003, 4(1), 45-58.
[75]Senapathy, J.G.; Jayanthi, S.; Viswanathan, P.; Umadevi, P.; Nalini, N. Effect of gallic acid on xenobiotic metabolizing enzymes in 1,2-dimethyl hydrazine induced colon carcinogenesis in Wistar rats – A chemopreventive approach. Food Chem Tox., 2011, 49, 887-892.

[76]Subramanian, A.P.; Jaganathan, S.K.; Mandal, M.; Supriyanto, E.; Muhamad, II. Gallic acid induced apoptotic events HCT-15 colon cancer cells. World J. Gastroenterol., 2016, 22(15), 3952-3961.
[77]Arndt, C.A.; Crist, W.M. Common musculoskeletal tumors of childhood and adolescence. N. Engl. J. Med., 1999, 341(5), 342- 352.
[78]Thompson, E.W.; Price, J.T. Mechanisms of tumour invasion and metastasis: Emerging targets for therapy. Expert Opin. Ther. Tar- gets, 2002, 6(2), 217-233.
[79]Liao, C.; Lai, K.; Huang, A.; Yang, J.; Lin, J.; Wug, S.; Woodh, W.G.; Lin, J.; Chung, J. Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the ma- trix metalloproteinase-2/-9, protein kinase B (PKB) and PKC sig- naling pathways. Food Chem. Tox., 2012, 50, 1734-1740.
[80]Dinarello, C.A. Anti-inflammatory agents: Present and future. Cell, 2010, 140(6), 935-950.
[81]Chen, H.; Ma, C.Y.; Chen, X.; Geng, Y.; Yang, C.; Jiang, H.Z.; Wang, X. The effect of rhein and gallic acid on the content of IL- 10, IL-1β and TNF-α in serum of rats with endotoxemia. J. Chem. Pharm. Res., 2014, 6(10), 296-299.
[82]Kim, S.H.; Jun, C.D.; Suk, K.; Choi, B.J.; Lim, H.; Park, S.; Lee, S.H.; Shin, H.Y.; Kim, D.K.; Shin, T.Y. Gallic acid inhibits hista- mine release and pro-inflammatory cytokine production in mast cells. Toxicol. Sci., 2006, 91(1), 123-131.
[83]Sanae, F.; Miyaichi, Y.; Hayashi, H. Endothelium-dependent con- traction of rat thoracic aorta induced by gallic acid. Phytother. Res., 2003, 17, 187-189.
[84]Kim, S.; Jun, C.; Suk, K.; Choi, B.; Lim, H.; Park, S.; Lee, S.; Shin, H.; Kim, D.; Shink, T. Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells. Toxicol. Sci., 2006, 91(1), 123-131.
[85]Das, N.D.; Jung, K.H.; Park, J.H.; Mondol, M.A.M.; Shin, H.J.; Lee, H.; Park, K.S.; Choi, M.R.; Kim, K.S.; Kim, M.S.; Lee, S.R.; Chai, Y.G. Terminalia chebula extract acts as a potential NF κβ inhibitor in human lymphoblastic T cells. Phytother. Res., 2011, 25, 927-934.
[86]Hsiang, C.; Hseu, Y.; Chang, Y.; Kumar, K.J.S.; Ho, T.; Yang, H. Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear factor-jB transgenic mice as evaluated by in vivo bioluminescence imaging. Food Chem., 2013, 136, 426-434.
[87]Liu, K.Y.P.; Hu, S.; Chan, B.C.L.; Wat, E.C.L.; Lau, C.B.S.; Hon, K.L.; Fung, K.P.; Leung, P.C.; Hui, P.C.L.; Lam, C.W.K.; Wong, C.K. Anti-Inflammatory and anti-allergic activities of pentaherb formula, moutan cortex (danpi) and gallic acid. Molecule, 2013, 18, 2483-2500.
[88]Yoon, C.; Chung, S.; Lee, S.; Park, Y.; Lee, S.; Park, M. Gallic acid, a natural polyphenolic acid, induces apoptosis and inhibits proinflammatory gene expressions in rheumatoid arthritis fibro- blast-like synoviocytes. Joint Bone Spine., 2013, 80, 274-279.
[89]Lin, Y.; Lin, J. (2)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide- in- duced activity of transcription factor nuclear factor-Kb. Mol. Pharmacol., 1997, 52, 465-472.
[90]Yang, F.; Villiers, W.J.S.; McClain, C.J.; Varilek, G.W. Green tea polyphenols block endotoxin-induced tumor necrosis factorproduc- tion and lethality in a murine model. J. Nutrit., 1998, 128(12), 2334-2340.
[91]Yang, F.; Oz, H.S.; Barve, S.; Villiers, W.J.S.D.E.; Mcclain, C.J.; Varilek, G.W. The green tea polyphenol (-)-epigallocatechin-3- gallate blocks nuclear factor-κb activation by inhibiting iκb kinase activity in the intestinal epithelial cell line IEC-6. Mol. Pharmacol., 2001, 60, 528-533.
[92]Vo, T.S.; Ngo, D.H.; Kim, S.K. Gallic acid-grafted chitooligosac- charides suppress antigen-induced allergic reactions in RBL-2H3 mast cells. Eur. J. Pharm. Sci., 2012, 47, 527-533.
[93]Youn, H.S.; Lee, J.Y.; Saitoh, S.I.; Miyake, K.; Kang, K.W.; Choi, Y.J.; Hwang, D.H. Suppression of MyD88-and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3- gallate, a polyphenol component of green tea. Biochem. Pharma- col., 2006, 72(7), 850-859.

[94]Karamac, M.; Kosiñska, A.; Pegg, R.B. Content of gallic acid in selected plant extracts. Pol. J. Food Nutr. Sci., 2006, 15(56), 55-58.
[95]Meshram, G.; Patil, B.; Yadav, S.; Shinde, D. Isolation and charac- terization of gallic acid from terminalia bellerica and its effect on carbohydrate regulatory system in vitro. Intl. J. Res. Ayurveda Pharm., 2011, 2(2), 559-562.
[96]Borges, A.; Ferreira, C.; Saavedra, M.J.; Simoes, M. Antibacterial activity and mode of action of ferulic and gallic acids against pathogenic bacteria. Microb. Drug Resist., 2013, 19(4), 256-65.
[97]Kang, M.; Oh, J.; Kang, I.; Hong, S.; Choi, C. Inhibitory effect of methyl gallate and gallic acid on oral bacteria. J. Microbiol., 2008, 46(6), 744-750.
[98]Lee, D.; Je, J. Gallic acid-Grafted-Chitosan inhibits foodborne pathogens by a membrane damage mechanism. J. Agric. Food Chem., 2013, 61(26), 6574-6579.
[99]Shibata, H.; Kondo, K.; Katsuyama, R.; Kawazoe, K.; Sato, Y.; Murakami, K.; Takaishi, Y.; Arakaki, N.; Higuti, T.Alkyl Gallates, Intensifiers of β-Lactam susceptibility in methicillin-resistant staphylococcus aureus. Antimicrob. Agents Chemother., 2005, 49(2), 549-555.
[100]Rangel, L.P.; Fritzen, M.; Yunes, R.A.; Leal, P.C.; Creczynski- Pasa, T.B.; Ferreira-Pereira, A. Inhibitory effects of gallic acid es- ter derivatives on Saccharomyces cerevisiae multidrug resistance proteinPdr5p. FEMS Yeast Res., 2010, 10, 244-251.
[101]Choi, H.J.; Song, J.H.; Bhatt, L.R.; Baek, S.H. Anti-Human rhino- virus activity of gallic acid possessing antioxidant capacity. Phy- tother. Res., 2010, 24, 1292-1296.
[102]Kratz, J.M.; Andrighetti-Fröhner, C.R.; Kolling, D.J.; Leal, P.C.; Cirne-Santos, C.C.; Yunes, R.A.; Nunes, R.J.; Trybala, E.; Berg- ström, T.; Frugulhetti, I.C.; Barardi, C.R.M.; Simões, C.M.O. Anti- HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate. Mem Inst Oswaldo Cruz, Rio de Janeiro., 2008, 103(5), 437-442.
[103]Kratz, J.M.; Andrighetti-Fröhner, C.R.; Kolling, D.J.; Leal, P.C.; Cirne-Santos, C.C.; Yunes, R.A.; Nunes, R.J.; Trybala, E.; Berg- ström, T.; Frugulhetti, I.C.; Barardi, C.R.M.; Simões, C.M.O. Evaluation of anti-HSV-2 activity of gallica and pentyl gallate. Biol. Pharm. Bull., 2008, 31(5), 903-907.
[104]Modi M.; Goel, T.; Das, T.; Malik, S.; Suri, S.; Rawat, A.K.S.; Srivastava, S.K.; Tuli, R.; Malhotra, S.; Gupta, S.K. Ellagic acid &
gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activ- ity. Indian J. Med. Res., 2013, 137, 540-548.
[105]Hamamura, Y.; Kuwata, K.; Masuda, H. Effect of gallic acid on growth of the silkworm larvae Bombyx Mori L. Nature, 1966, 212, 1386-1387.
[106]Chandra, R.P.; Lehtonen, L.K.; Ragauskas, A.J. Modification of high lignin content kraft pulps with laccase to improve paper strength properties, laccase treatment in the presence of gallic acid. Biotechnol. Prog., 2004, 20, 255-261.
[107]Jung, S.; Choe, J.H.; Kim, B.; Yun, H.; Kruk, Z.A., Jo, C. Effect of dietary mixture of gallic acid and linoleic acid on antioxidative po- tential and quality of breast meat from broilers. Meat Sci., 2010, 86, 520-526.
[108]Jeon, J.; Kim, E.; Murugesan, K.; Park, H.; Kim, Y.; Kwon, J.; Kim, W.; Lee, J.; Chang, Y. Laccase-catalysed polymeric dye syn- thesis from plant-derived phenols for potential application in hair dyeing: Enzymatic colourations driven by homo- or hetero-polymer synthesis. Microbial. Biotechnol., 2010, 3(3), 324-335.
[109]Jung, S.; Han, B.H.; Nam, K.; Ahn, D.U.; Lee, J.H.; Jo, C. Effect of dietary supplementation of gallic acid and linoleic acid mixture or their synthetic salt on egg quality. Food Chem., 2011, 129, 822-829.
[110]Neo, Y.P.; Swift, S.; Ray, S.; Gizdavic-Nikolaidis, M.; Jin, J.; Perera, C.O. Evaluation of gallic acid loaded zein sub-micron elec- trospun fibre mats as novel active packaging materials. Food Chem., 2013, 141, 3192-3200.
[111]Ghosh, M.; Pal, A.K. Radio protective activity of gallic acid in a bacterial system. J. Nat. Pharm., 2011, 2(4), 210-213.
[112]Khatkar, A.; Nanda, A.; Narasimhan, B. Evaluation of preservative effectiveness of gallic acid derivatives in aluminium hydroxide gel- USP. Chronicles Young Scient., 2013, 4(2), 148-152.